EP2276742B1 - Bromhydrate d'ivabradine - Google Patents

Bromhydrate d'ivabradine Download PDF

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Publication number
EP2276742B1
EP2276742B1 EP09731459.5A EP09731459A EP2276742B1 EP 2276742 B1 EP2276742 B1 EP 2276742B1 EP 09731459 A EP09731459 A EP 09731459A EP 2276742 B1 EP2276742 B1 EP 2276742B1
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Prior art keywords
ivabradine
hydrobromide
weight
ivabradine hydrobromide
tablets
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EP2276742A1 (fr
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Matej Smrkolj
Urska Gojak
Berta Kotar-Jordan
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KRKA dd
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KRKA Tovarna Zdravil dd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to ivabradine hydrobromide of formula (I), to processes for its preparation and to pharmaceutical compositions containing it.
  • Ivabradine and addition salts thereof with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
  • the preparation and therapeutic use of ivabradine hydrochloride have been described in EP534859 .
  • New crystalline forms of ivabradine hydrochloride have been described in EP1589005 , EP1695710 , EP1695709 , EP1707562 , EP1695965 , EP1775288 and EP1775287 .
  • the X-ray powder diffraction pattern was obtained by Philips PW3040/60 X'Pert powder diffractometer, X'celerator detector at CuK ⁇ radiation, 1.54178 ⁇ , 3° ⁇ 2 ⁇ 30°.
  • FT-IR spectra (KBr discs) were recorded over the wave number range of 4000-400 cm -1 on Perkin Elmer FT-IR spectrometer Spectrum 100 at a resolution 4 cm -1 .
  • the size distribution of ivabradine hydrobromide particles was determined by laser diffraction using a Malvern Mastersizer 2000 laser diffraction instrument.
  • the samples for analysis were prepared by dispersing a weighed amount of ivabradine hydrobromide particles in isopar.
  • UPLC chromatogram of related substances of ivabradin was obtained on an ultra performance liquid chromatograph with UV detector. Chromatographic separation was achieved using ACQUITY UPLC BEH HSS T3, 2.1x100mm, 1.7 ⁇ m analytical column. Chromatographic conditions used were: sample concentration of 1.0mg/ml, detection at 286 nm, flow of 0.4ml/min, volume of injection 5 ⁇ L. A gradient elution using mobile phase A (0.01M CH 3 COONH 4 pH 7.5) and mobile phase B (CH 3 CN) was employed with time table (0min 5%B, 30min 60%B, 32min 5%B, 37min 5%).
  • the present invention relates to the ivabradine hydrobromide in a solid or dissolved state.
  • Solid ivabradine hydrobromide can be in an amorphous or crystalline state.
  • Crystalline ivabradine hydrobromide prepared according to present invention is characterized by an X-ray powder diffraction pattern having peaks at about 13.2, 15.8, 16.8, 21.1, 24.5 ⁇ 0.2 degrees two-theta.
  • Crystalline ivabradine hydrobromide can be further characterized by X-ray powder diffraction peaks at about 13.2, 15.8, 16.8, 21.1, 24.5, 25.7, 26.3, 27.7 ⁇ 0.2 degrees two-theta. It may either be more than 90, 95%, 99%, 99.5% or 99.9% of polymorphic purity or include other polymorphic, or an amorphous form.
  • the X-ray powder diffraction pattern of crystalline ivabradine hydrobromide is shown in Figure 1 .
  • the new salt of ivabradine according to present invention can be prepared by common methods used in the preparation of amine salts.
  • Crystalline ivabradine hydrobromide can be prepared by cooling solution of ivabradine hydrobromide to precipitate crystalline ivabradine hydrobromide.
  • Crystalline or amorphous ivabradine hydrobromide can also be prepared by evaporating the solvent from ivabradine hydrobromide solution or by addition of antisolvent to ivabradine hydrobromide solution.
  • Suitable solvents for preparation of ivabradine hydrobromide can be selected from the group consisting of water, nitriles, ketones, esters, ethers, alcohols, sulfoxides, amides, halogenated hydrocarbons or/and any mixture thereof.
  • the solvent is water, methanol, ethanol, acetonitrile, DMSO, acetone, ethyl methyl ketone, ethyl acetate, i-propyl acetate, methylen chloride or/and any mixture thereof.
  • Ivabradine solutions or suspensions can be prepared by mixing the solution of ivabradine and a solution of hydrogen bromide.
  • Hydrogen bromide solution is preferably aqueous or alcoholic solution, most preferably aqueous solution such as 48% aqueous solution.
  • Step (i) is preferably performed at a temperature within the range of 20 to 25°C.
  • the process preferably comprises the following additional steps:
  • Drying is preferably performed under vacuum. It is also preferred to dry the product at a temperature within a range of from 35 to 65 °C, more preferably 45 to 55 °C and most preferably at about 50°C. During drying the product can be sieved to deagglomerate and/or remove lumps.
  • Ivabradine base used in the present invention can be prepared according to methods disclosed in EP534859 and can also be further recrystallized and/or purified to a purity level more than 99%, 99.5% or 99.9 %. If the ivabradine hydrobromide prepared by the present invention is not satisfactorily pure, it can be recrystallized to a purity level more than 99%, 99.5% or 99.9 %, determined by UPLC on an Atlantis T3 UPLC column 150 x 4,6 mm 3 ⁇ m particles, detection at 286 nm, flow rate 1.0 ml/min, column temperature 45°C, injection volume 5 ⁇ l, gradient elution, mobile phase: ammonium acetate (A) and acetonitrile (B).
  • A ammonium acetate
  • B acetonitrile
  • Ivabradine hydrobromide prepared according to present invention can be in an anhydrous or hydrated form.
  • the hydrated form of ivabradine hydrobromide preferably has a water content of 1.0-6.0 % (w/w), more preferably 2.0-5.0 % (w/w), most preferably 2.0-4.0 % (w/w). Water content is determined by Karl Fisher method.
  • the average particle size of ivabradine hydrobromide prepared according to the present invention can be in the range of 0.1-600 ⁇ m, preferably 0.3 - 300 ⁇ m, most preferably 0.5 - 150 ⁇ m.
  • Particle size is determined by laser diffraction method on Malvern Mastersizer 2000 instrument equiped with Hydro S dispersion unit, which is appropriate for measuring particle size distributions in the range of 20nm to 2000 ⁇ m.
  • Isopar L is used as dispersant. Usually, 100-800mg of substance is dispersed in 5-10 ml of 2% solution of epicurone (lecithin) in isopar L to get homogenuous sample suspension. The measurement is started after addition of sample suspension into dispersion unit. If agglomerates are present, homogenizing by sonication for appropriate time is used to brake-up agglomerates followed by recirculating at stirrer/pump speed rate about 40-70% of max. speed.
  • average particle size refers to the volume mean particle diameter, determined by laser light scattering using a Malvern Mastersizer instrument 2000.
  • the obtained ivabradine hydrobromide can be sieved, milled or micronized optionally together with other excipients. In the case of agglomerates, ultrasonication can be used.
  • the present invention also relates to pharmaceutical compositions containing ivabradine hydrobromide as active ingredient in admixture with one or more carriers or auxiliary substance(s) conventionally applied in the pharmaceutical industry.
  • compositions according to the invention usually contain 1 - 90 % by weight, preferably 1 - 50 % by weight, most preferably 1 - 15 % by weight of active ingredient. Further, pharmaceutical compositions contain an amount of ivabradine hydrobromide, corresponding to 1-30 mg ivabradine per dosage unit. Most preferably, pharmaceutical compositions according to the present invention contain an amount of ivabradine hydrobromide, corresponding to 5 mg and 7.5 mg of ivabradine per dosage unit.
  • compositions of the present invention may be suitable for oral (for example powders, pellets, tablets, coated tablets, capsules, orally disintegrating tablets, chewable tablets, solutions, suspensions or emulsions), parenteral (for example injection solutions for intravenous, intramuscular, subcutaneous or intraperitoneal use), rectal (suppositories), transdermal (patches) or local (ointments or patches) administration or for the application in form of implants.
  • a tablet for oral administration is preferred pharmaceutical dosage form.
  • the solid pharmaceutical compositions containing ivabradine hydrobromide further comprise at least one more auxiliary agent selected from the group of fillers or carriers, binding agents, disintegrants, stabilizers, lubricants, glidants, surface active agents, sweetening agents, flavours etc.
  • Diluents may be selected (but are not limited to) from the group of lactose in different forms (anhydrous, monohydrate, spray dried lactose etc.), microcrystalline cellulose (such as commercially available Avicel PH 101, Avicel PH 102 or Avicel PH 112), powdered cellulose, Cellactose (mixture of lactose and cellulose powder), silicified microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, sucrose, glucose, fructose, dextrates, maltodextrins, other sugars such as mannitol, lactitol, xylitol, sorbitol, calcium lactate or combined diluents. Starches such as pregelatinized starch, can also be used as a diluent.
  • Suitable binder may be selected from the group consisting of microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or other cellulose ethers, dextrates, maltodextrin, povidone (polyvinylpyrrolidone), polyethylene glycol, starch, pregelatinized starch, gelatine, polymethacrylate.
  • disintegrants and/or superdisintegrants may also be included into pharmaceutical composition, such as starches (e.g. maize starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked carboxymethlycellulose sodium), cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline cellulose, carboxymethylcellulose sodium, Amberlite ® (polacrilin potassium), alginic acid, sodium alginate, guar gum, gellan gum, xantan gum or calcium silicate.
  • starches e.g. maize starch, potato starch
  • modified starches sodium starch glycolate
  • modified cellulose croscarmellose, i.e. cross-linked carboxymethlycellulose sodium
  • crospovidone cross-linked polyvinylpyrrolidone
  • microcrystalline cellulose carboxymethylcellulose sodium
  • Amberlite ® polyacrilin potassium
  • alginic acid sodium alginate
  • pharmaceutical composition may contain stabilizers, such as cellulose derivatives, polyvinylpyrrolidone and derivatives thereof, xantan gum, pectins, alginates, tragacanth, arabic gum, carrageenans, agar, bentonite, cyclodextrins, sodium hydrogen carbonate, calcium carbonate, calcium chloride, magnesium oxide, magnesium hydroxide, magnesium aluminium silicate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium acetate, sodium tartrate or any other stabilizer.
  • stabilizers such as cellulose derivatives, polyvinylpyrrolidone and derivatives thereof, xantan gum, pectins, alginates, tragacanth, arabic gum, carrageenans, agar, bentonite, cyclodextrins, sodium hydrogen carbonate, calcium carbonate, calcium chloride, magnesium oxide, magnesium hydroxide, magnesium aluminium silicate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium acetate,
  • the pharmaceutical composition of the present invention may contain lubricants.
  • Suitable lubricants are stearic acid, magnesium stearate, calcium stearate, sodium laurylsulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols.
  • a preferred lubricant is magnesium stearate or sodium stearyl fumarate.
  • Glidants can also be added to the composition according to the invention. They can be selected from the group comprising of talc, silicon dioxide of different grades (such as colloidal or precipitated silica) etc.
  • Excipients may have multiple functions, i.e. one excipient may be diluent and additionally binder, binder and disintegrant etc.
  • compositions according to the present invention comprise:
  • a process for the preparation of the pharmaceutical compositions containing hydrobromide which comprises admixing said active ingredient with at least one carrier(s) or auxiliary substance(s) conventionally applied in the pharmaceutical industry.
  • Any suitable process for the preparation of the tablets for oral administration may be applied, e.g. direct compression, wet (water or alcohol) or dry granulation etc.
  • cores/tablets can be coated with conventional materials used for film coating, i.e. as described in Pharmaceutical Coating Technology (G. Cole (ed.), 1995).
  • Film coating formulations usually contain the following components:
  • the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers (e.g. hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose), or acrylic polymers and copolymers. Occasionally, high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials are used. Usually their function is to prevent bad mouth feel and/or taste and in some cases degradation, e.g. oxidation of the active ingredients and/or excipients used.
  • plasticizers are polyols (glycerol, propylene glycol, polyethylene glycols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin) and oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
  • Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours.
  • Film coating dispersions can also be used as ready-to-make preparations which are available on the market.
  • Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
  • composition of coating dispersion (calculated on dry material) which comprises:
  • the mass ratio of coating to core is preferably from 0.01:1 to 0.05:1, most preferably from 0.02:1 to 0.04:1.
  • the pharmaceutical composition of ivabradine hydrobromide might be processed and packed under a modified atmosphere.
  • the atmosphere with the modified oxygen content or reduced oxygen partial pressure may be obtained by the use of a reduced pressure atmosphere, e.g. by creating a partial vacuum by means of a suitable pump or by partial freezing or liquefying the atmosphere, or by the use of an inert gas, such as nitrogen or argon, or by the use of oxygen absorbents, even though the high efficacy of such absorbents leading to very low oxygen levels is normally not necessary.
  • the composition is present in a packaging, with a blister packaging or a bottle being preferred.
  • the packaging can be provided with means for trapping and disposal of free oxygen.
  • the composition might be enclosed in a substantially gas exchange non-permeable material as packaging which has an atmosphere with the required reduced oxygen content.
  • the substantially gas exchange non-permeable packaging is preferably selected from the group consisting of an Al/Al blister package, an Al-polychloro-3-fluoroethylene homopolymer/PVC laminate blister or a bottle.
  • ivabradine hydrobromide as amorphous form 1.5 g was suspended in 10 ml of acetonitrile, heated to temperature of reflux, mixed for 10 minutes and gradually cooled to 20-25°C. The product was filtered, washed with acetonitrile and dried in a vacuum dryer at final temperature 40°C. 1.1 g of crystalline ivabradine hydrobromide hydrate was obtained (assay of water 3.7%).
  • Example 5 7.5 mg tablets
  • Ivabradine hydrobromide, lactose monohydrate and microcrystalline cellulose were homogeneously mixed in a suitable mixer.
  • suitable stabilizer may be included.
  • Colloidal silicon dioxide and magnesium stearate were added in the end and lubricated compression mixture was pressed into tablets.
  • tablets are coated with the coating dispersion.
  • Example 6 7.5 mg tablets
  • Ivabradine hydrobromide, maize starch, Cellactose and pregelatinized starch were homogeneously mixed in a suitable mixer.
  • suitable stabilizer may be included.
  • Magnesium stearate was added in the end and lubricated compression mixture was pressed into tablets.
  • tablets are coated with the coating dispersion.
  • Example 7 7.5 mg tablets
  • Ivabradine hydrobromide, lactose monohydrate, microcrystalline cellulose, PVP K30, crospovidone and colloidal silicon dioxide were homogeneously mixed in a suitable mixer. Magnesium stearate was added in the end and lubricated compression mixture was pressed into tablets. Optionally, tablets are coated with the coating dispersion
  • Example 8 7.5 mg tablets
  • Ivabradine hydrobromide, lactose monohydrate, microcrystalline cellulose, PVP K30 and colloidal silicon dioxide were homogeneously mixed in a suitable mixer. Magnesium stearate was added in the end and lubricated compression mixture was pressed into tablets. Tablets were film-coated, either with the coating composition presented in the following table or with coating system Opadry ® . Film-coating Amount/tablet [mg] Hypromellose 6cp 3.000 Polyethylene glycol 6000 0.480 Glycerol 0.195 Titanium dioxide 0.675 Iron oxide, yellow 0.090 Iron oxide, red 0.030 Magnesium stearate 0.030 Total 4.5
  • Example 9 7.5 mg tablets
  • Ivabradine hydrobromide, lactose monohydrate, microcrystalline cellulose, PVP K30, croscarmellose sodium and colloidal silicon dioxide were homogeneously mixed in a suitable mixer. Magnesium stearate was added in the end and lubricated compression mixture was pressed into tablets. Optionally, tablets are film coated with the aqueous coating dispersion in a suitable coating pan.
  • Example 10 7.5 mg tablets
  • Ivabradine hydrobromide, lactose monohydrate, microcrystalline cellulose, L-HPC LH 11, croscarmellose sodium and colloidal silicon dioxide were homogeneously mixed in a suitable mixer. Magnesium stearate was added in the end and lubricated compression mixture was pressed into tablets. Optionally, tablets are film coated with the aqueous coating dispersion in a suitable coating pan.
  • Example 11 7.5 mg tablets
  • Ivabradine hydrobromide, maize starch, lactose monohydrate and maltodextrin were homogeneously mixed in a suitable mixer.
  • suitable stabilizer may be included.
  • the obtained mixture was granulated with granulating liquid (purified water, alcohol).
  • the wet granulate was dried, sieved and mixed with colloidal silicon dioxide and magnesium stearate.
  • Lubricated compression mixture was pressed into tablets.
  • tablets are coated with the coating dispersion in a suitable coating pan.
  • Example 12 7.5 mg tablets
  • the mixture of ivabradine hydrobromide, lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone and optionally stabilizer was wetted with granulating liquid (purified water, alcohol) and kneaded. The wet granules were dried and sieved. In the end colloidal silicon dioxide and magnesium stearate were added to the dry granulate and the obtained compression mixture was compressed into tablets. Optionally, tablets are coated with the coating dispersion in a suitable coating pan.
  • Example 13 7.5 mg tablets
  • the mixture of ivabradine hydrobromide, lactose monohydrate, hydroxypropylcellulose and optionally stabilizer was wetted with granulating liquid (purified water, alcohol) and kneaded. The wet granules were dried and sieved. Microcrystalline cellulose and colloidal silicon dioxide were added to the dry granulate. Magnesium stearate was admixed and the obtained compression mixture was compressed into tablets. Optionally, tablets are coated with the coating dispersion in a suitable coating pan.
  • Example 14 7.5 mg tablets
  • Ivabradine hydrobromide was mixed in a suitable mixer with all other excipients (except a part of crospovidone and a part of magnesium stearate).
  • suitable stabilizer may be included.
  • the mixture was compacted with roller compactor, the obtained compacts were milled and sieved, blended with the remaining crospovidone and magnesium stearate and compressed into tablets.
  • tablets are coated with the coating dispersion in a suitable coating pan.
  • Example 15 7.5 mg tablets
  • Ivabradine hydrobromide was mixed in a suitable mixer with all other excipients except magnesium stearate.
  • suitable stabilizer may be included.
  • the mixture was compacted with roller compactor, the obtained compacts were milled and sieved, blended with magnesium stearate and compressed into tablets.
  • tablets are coated with the coating dispersion in a suitable coating pan.

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Claims (10)

  1. Bromhydrate d'ivabradine sous forme cristalline, caractérisé en ce que son diagramme de diffraction des rayons X à l'état de poudre, déterminé avec la raie Kα du cuivre de longueur d'onde 0,154178 nm, comporte des pics pour les valeurs de 13,2°, 15,8°, 16,8°, 21,1°, 24,5° et 25,7°, à ± 0,2° près, de l'angle 2θ.
  2. Bromhydrate d'ivabradine conforme à la revendication 1, caractérisé en outre en ce qu'il donne des pics pour les valeurs de 13,2°, 15,8°, 16,8°, 21,1°, 24,5°, 25,7°, 26,3° et 27,7°, à ± 0,2° près, de l'angle 2θ.
  3. Bromhydrate d'ivabradine conforme à l'une des revendications précédentes, présentant une taille moyenne de particules de 0,1 à 600 µm, et de préférence de 0,3 à 300 µm.
  4. Bromhydrate d'ivabradine conforme à l'une des revendications précédentes, comprenant de 1,0 à 6,0 % en poids d'eau.
  5. Composition pharmaceutique comprenant du bromhydrate d'ivabradine, conforme à l'une des revendications précédentes, et des excipients pharmacologiquement admissibles.
  6. Composition pharmaceutique conforme à la revendication 5, comprenant de 1 à 90 % en poids, de préférence de 1 à 50 % en poids, et mieux encore de 1 à 15 % en poids, de bromhydrate d'ivabradine.
  7. Composition pharmaceutique conforme à la revendication 6, comprenant :
    - de 5 à 20 % en poids, de préférence de 5 à 10 % en poids, et mieux encore de 5 à 7 % en poids, de bromhydrate d'ivabradine,
    - de 20 à 95 % en poids, de préférence de 60 à 93 % en poids, et mieux encore de 60 à 90 % en poids, d'un diluant,
    - de 0 à 40 % en poids, de préférence de 0 à 30 % en poids, et mieux encore de 2 à 26 % en poids, d'un liant,
    - de 0 à 40 % en poids, de préférence de 0 à 30 % en poids, et mieux encore de 2 à 20 % en poids, d'un délitant,
    - de 0 à 3 % en poids, de préférence de 0,5 à 2 % en poids, et mieux encore de 0,5 à 1 % en poids, d'un lubrifiant,
    - et de 0 à 2 % en poids, de préférence de 0,1 à 1 % en poids, et mieux encore de 0,1 à 0,5 % en poids, d'un agent de glissement,
    par rapport au poids total de la composition.
  8. Composition pharmaceutique conforme à l'une des revendications 5 à 7, comprenant un enrobage pelliculaire.
  9. Composition pharmaceutique conforme à la revendication 8, dans laquelle l'enrobage pelliculaire comprend :
    - de 1 à 99 % en poids, et de préférence de 1 à 95 % en poids, d'un polymère,
    - de 1 à 50 % en poids, et de préférence de 1 à 40 % en poids, d'un plastifiant,
    - et de 0,1 à 20 % en poids, et de préférence de 0,1 à 10 % en poids, d'un agent colorant et/ou opacifiant,
    par rapport au poids total de l'enrobage.
  10. Procédé de préparation de bromhydrate d'ivabradine conforme à l'une des revendications 1 à 3, comportant les étapes suivantes :
    i) dissoudre de l'ivabradine dans un solvant approprié, et de préférence, dans du chlorure de méthylène ;
    ii) ajouter une solution de bromure d'hydrogène, de préférence une solution alcoolique ou mieux encore une solution aqueuse, le mieux étant une solution aqueuse à 48 % de bromure d'hydrogène ;
    iii) chasser le solvant par évaporation à siccité, de préférence sous vide ;
    et en option,
    iv) redissoudre ou disperser le produit issu de l'étape (iii) dans un deuxième solvant, et de préférence, dans de l'acétate d'éthyle ;
    v) maintenir le mélange issu de l'étape (iv) à une température de 20 à 25 °C durant 8 à 16 heures, et de préférence, durant 12 heures ;
    vi) isoler le produit, de préférence par filtration ;
    vii) en option, laver le produit issu de l'étape (vi) avec un solvant, et de préférence, avec du même solvant que celui utilisé dans l'étape (iv), en particulier de l'acétate d'éthyle ;
    viii) et faire sécher le produit issu de l'étape (vii).
EP09731459.5A 2008-04-07 2009-04-07 Bromhydrate d'ivabradine Active EP2276742B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI200800080A SI22750A (sl) 2008-04-07 2008-04-07 Ivabradin hidrobromid
PCT/EP2009/054159 WO2009124940A1 (fr) 2008-04-07 2009-04-07 Bromhydrate d'ivabradine

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EP2276742A1 EP2276742A1 (fr) 2011-01-26
EP2276742B1 true EP2276742B1 (fr) 2014-01-22

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EP (1) EP2276742B1 (fr)
EA (1) EA017553B1 (fr)
SI (1) SI22750A (fr)
UA (1) UA103996C2 (fr)
WO (1) WO2009124940A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2162438A4 (fr) 2007-05-30 2011-07-06 Ind Swift Lab Ltd Procédé de préparation de chlorhydrate d'ivabradine et polymorphe correspondant
HUP1000245A2 (en) 2010-05-07 2011-11-28 Richter Gedeon Nyrt Industrial process for the production ivabradin salts
WO2011157721A2 (fr) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Composition pharmaceutique contenant de l'ivabradine
EP2948432B1 (fr) 2013-01-24 2018-09-19 Synthon BV Procédé de préparation d'ivabradine
PT2774606T (pt) 2014-02-14 2019-05-06 Synthon Bv Composição farmacêutica compreendendo polimorfo de cloridrato de ivabradina iv
EP3025705B8 (fr) 2014-11-25 2018-11-28 Sanofi Ilaç Sanayi ve Ticaret Anonim Sirketi Formulations d'ivabradine stable
CN109939239B (zh) * 2017-12-19 2022-08-23 江苏恒瑞医药股份有限公司 药物组合物及其制备方法

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FR2681862B1 (fr) * 1991-09-27 1993-11-12 Adir Cie Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent.
FR2868777B1 (fr) * 2004-04-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

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EA017553B1 (ru) 2013-01-30
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SI22750A (sl) 2009-10-31
EA201001353A1 (ru) 2011-04-29
EP2276742A1 (fr) 2011-01-26

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